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Roche’s Perjeta recommended for approval in EU for use before surgery in HER2-positive early breast cancer

On June 26, 2015 Roche reported that the EU Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission approves the use of Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and chemotherapy for the neoadjuvant treatment (use before surgery) of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence (Press release, Hoffmann-La Roche , JUN 26, 2015, View Source [SID:1234505808]).

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The EU filing was based primarily on data from the Phase II NeoSphere study, which showed that nearly 40% of people receiving the Perjeta regimen had no evidence of tumour tissue detectable at the time of surgery in the affected breast and local lymph nodes (known as a pathological complete response, or pCR) compared to 21.5% of people who received Herceptin and taxane chemotherapy alone. 1 This is the first CHMP recommendation in the neoadjuvant setting based on pCR.

Every year, approximately 100,000 people in Europe are diagnosed with HER2-positive breast cancer, an aggressive type of the disease that is likely to progress more quickly than cancer that is HER2-negative. 2,3 The majority of breast cancer cases are diagnosed at an early stage of the disease, before the cancer has spread to other parts of the body. 4,5

"Breast cancer treatment has the greatest impact in the early stage, where it can potentially prevent the disease from returning and spreading. Consequently, there is a need to bring promising treatments to patients with early breast cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are very pleased that the use of pCR as a novel clinical trial endpoint may hopefully soon allow us to make the Perjeta regimen available to patients with early breast cancer in Europe."

The CHMP opinion was provided in the context of the totality of Perjeta data available to date, including the biological rationale for the combination of Perjeta, Herceptin and taxane chemotherapy, its established safety profile and the efficacy results in the advanced breast cancer (aBC) setting. The submission was supported by efficacy and safety data from two neoadjuvant studies, NeoSphere and TRYPHAENA, as well as long-term safety results from the CLEOPATRA trial in people with previously untreated HER2-positive aBC. Data from the ongoing Phase III APHINITY study in the adjuvant (post-surgery) setting will provide additional insights into the broader role of Perjeta in the treatment of HER2-positive early breast cancer (eBC).

Perjeta is already approved as a neoadjuvant treatment for people with HER2-positive eBC in the U.S. and 20 other countries.

Follow-up data from the NeoSphere study were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Annual Meeting. 6 These data suggest that, at three years, people who received the Perjeta regimen prior to surgery were 31% less likely to experience disease worsening, recurrence or death (progression-free survival, PFS HR=0.69; 95% CI, 0.34–1.40) compared to those who received Herceptin and chemotherapy.6 People treated with the Perjeta regimen were also 40% less likely to experience disease recurrence or death (disease-free survival, DFS HR=0.60; 95% CI, 0.28–1.27). 6

About the NeoSphere trial
The NeoSphere trial1 (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomised, multicentre, international Phase II study in 417 people with newly diagnosed HER2-positive, operable, locally advanced or inflammatory eBC. Participants were randomised to one of four study arms and received four cycles (12 weeks) of neoadjuvant treatment followed by surgery and a year of adjuvant treatment with Herceptin plus chemotherapy. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, DFS, PFS, breast-conserving surgery rate and biomarker assessment. Study data showed the following:

Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of pCR in the breast and local lymph nodes by 17.8% compared to Herceptin and chemotherapy alone (39.3% vs. 21.5%, p=0.0063).
pCR of 21.5% for Herceptin and chemotherapy

pCR of 39.3% for Perjeta, Herceptin and chemotherapy

pCR of 11.2% for Perjeta and Herceptin

pCR of 17.7% for Perjeta and chemotherapy

The Perjeta regimen was not associated with a significant increase in adverse events (AEs), compared to Herceptin and chemotherapy alone.

The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9%), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4%), leukopenia (decrease in overall white blood cells, 4.7%) and diarrhoea (5.6%).

pCR means that there is no tumour tissue detectable at the time of surgery either in the affected breast or in the affected breast and local lymph nodes following completion of neoadjuvant treatment.

About the TRYPHAENA trial
The TRYPHAENA trial7 (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer) is a randomised, multicentre Phase II study that was conducted in 225 people with HER2-positive, operable, locally advanced or inflammatory eBC with tumours greater than two centimetres. Participants were randomised to one of three neoadjuvant Perjeta regimens. The primary endpoint was cardiac safety. Secondary endpoints included pCR, clinical response, breast-conserving surgery rate, DFS, PFS, overall survival (OS) and biomarker assessment. Study data showed the following:

The study was not powered to compare the three study arms. The rates of total pCR in the breast and local lymph nodes in the three arms were as follows:

pCR of 56.2% for Perjeta, Herceptin and anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy

pCR of 54.7% for anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy

pCR of 63.6% for the anthracycline-free arm (Perjeta, Herceptin, chemotherapy and carboplatin chemotherapy)

No new or unexpected cardiac AEs, or other AEs, were observed in any of the study arms. AEs observed were consistent with those seen in previous studies of Perjeta, Herceptin and chemotherapy, either in combination or alone.

The most common severe (Grade 3 or higher) AEs in any of the three study arms were:
In the concurrent arm: neutropenia (47.2%), leukopenia (19.4%) and febrile neutropenia (18.1%)

In the sequential arm: neutropenia (42.7%), leukopenia (12.0%), febrile neutropenia (9.3%), diarrhoea (5.3%) and left ventricular dysfunction (4.0%)

In the anthracycline-free arm: neutropenia (46.1%), febrile neutropenia (17.1%), anaemia (decrease in red blood cells, 17.1%); the AEs of diarrhoea, leukopenia, anaemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8%

About Roche’s medicines for HER2-positive breast cancer

Roche has been leading research into the HER2 pathway for over 30 years and is committed to improving the health, quality of life and survival for people with both early and advanced HER2-positive disease.

Roche has developed three innovative medicines that have helped transform the treatment of HER2-positive breast cancer:
Herceptin, Perjeta and Kadcyla. HER2-positive breast cancer is a particularly aggressive form of the disease that affects approximately 20% of patients.3 Over the past 15 years, the outlook for people with HER2-positive disease has improved to the extent that those with this form of the disease treated with these innovative medicines now typically experience better outcomes than people with less aggressive HER2-negative disease. 8

Eligibility for treatment with Roche’s HER2-targeted medicines is determined via a diagnostic test, saving time from the outset by identifying patients who will likely benefit from these medicines at the onset of their disease.

Cantargia licenses BioWa POTELLIGENT Technology platform for production of lead product candidate

On June 26, 2015 Cantargia reported that it has acquired a non-exclusive license to the POTELLIGENT Technology platform for the production of the proprietary product candidate CAN04 (Press release, Kyowa Hakko Kirin, JUN 26, 2015, View Source [SID:1234505807]). The POTELLIGENT Technology platform has been designed for research and development of antibody dependent cellular cytotoxicity (ADCC) enhanced antibodies. Commercial details of the agreement were not disclosed.

The POTELLIGENT Technology platform will be used to produce Cantargia’s lead product candidate, the monoclonal antibody CAN04 directed against the target molecule IL1RAP. The molecule IL1RAP is expressed on both cancer stem cells and mature cancer cells. CAN04 has a mode of action combining the blocking of IL-1 signaling in the cancer cell and ADCC. By using the POTELLIGENT Technology platform, a significantly enhanced ADCC activity can be obtained leading to increased efficacy.

"By utilizing BioWa’s POTELLIGENT Technology, CAN04 can be produced with significantly higher potency than normally obtained in a standard production system", says Göran Forsberg, CEO of Cantargia. "This will be a very important tool to augment the antitumor activity of CAN04 that enables state-of-the-art production technology".

"We are extremely pleased that the value of our POTELLIGENT Technology continues to be recognized by innovative companies such as Cantargia for their antibody programs in oncology," said Yasunori Yamaguchi, President and CEO of BioWa." We are very excited to work together with Cantargia on their promising antibody program".

Invenra and Oxford BioTherapeutics Enter Collaboration to Discover Novel Therapeutic Antibodies Targeting Cancer

On June 15, 2015 Invenra, Inc., a pre-clinical stage bio-pharmaceutical company focused on next-generation therapeutic human antibodies and antibody derivatives, and Oxford BioTherapeutics (OBT), an international, clinical stage biotechnology company developing a range of innovative antibody-based therapeutics for cancer, reported a collaboration to identify and characterize a panel of fully human therapeutic monoclonal antibodies (mAbs) against a novel cancer target that OBT has identified utilizing its OGAP discovery platform (Press release, Invenra, JUN 25, 2015, View Source [SID1234570590]).

Under the terms of the agreement, OBT will make an initial payment to Invenra upon successful delivery of a panel of novel mAbs confirmed to meet mutually agreed design goals and specifications. OBT will be responsible for all further development of the therapeutic product candidates. Assuming successful development, Invenra could receive further milestone payments and royalties on net sales of therapeutic and diagnostic products. In addition, OBT obtains diagnostic product rights from Invenra and will have the option of developing diagnostic products. Further financial details of the deal were not disclosed.

Invenra’s proprietary platform is based on ultra-high throughput technology to synthesize hundreds of thousands of full-length antibodies via cell-free expression and release them into nanowells, where they can be directly and quickly interrogated against cells in a multi-plexed fashion with a diverse set of immunotypic and biologically relevant assays. The Invenra technology allows rapid identification of high affinity mAbs with the broadest epitope coverage possible while simultaneously performing direct phenotypic screening to isolate those mAbs with the most relevant biological activity, thus leading to the selection of the best lead compounds for further development.

OBT’s proprietary target discovery platform, OGAP (Oxford Genome Anatomy Project), incorporates one of the world’s largest proprietary cell-membrane focused proteomic databases, with data on over 5,000 cancer membrane proteins providing unique, highly-qualified oncology targets that are selected for optimal ADC activity.

Keith Wilson, OBT’s chief scientific officer, said, "OBT is passionate about developing targeted cancer therapies for patients, and we are excited to be working with Invenra on a new approach to pursue mAb-based therapies. This collaboration leverages the complementary expertise of our two companies in identifying optimal mAbs against targets differentially expressed in cancer."

Roland Green, CEO and president of Invenra, said, "This collaboration is a major milestone for Invenra as a company and a validation of our innovative technology. We are delighted to be collaborating with Oxford BioTherapeutics to identify best-in-class antibodies against their novel oncology target. In addition, this collaboration with OBT fits well within our business model, whereby we are making our technology available to a select group of companies while continuing to develop our own internal proprietary pipeline of therapeutic product candidates."

TESARO Announces Six Abstracts to be Presented at the 2015 Multinational Association of Supportive Care in Cancer Annual Meeting

On June 25, 2015 TESARO reported the presentation of six abstracts at the 2015 Multinational Association of Supportive Care in Cancer (MASCC/ISOO) Annual Meeting, June 25 to 27, 2015, in Copenhagen (Press release, TESARO, JUN 25, 2015, View Source [SID:1234505804]).

Presentation Details:

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of highly- or moderately emetogenic chemotherapy (HEC; MEC)
Abstract: 11-03-O, Oral Presentation, Friday, June 26, 2015 from 5:45 PM to 7:15 PM

Impact of rolapitant on quality of life (QoL) in patients (pts) receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC)
Abstract: 11-38-P, Poster Presentation, Friday, June 26, 2015

Rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline/cyclophosphamide (A/C) moderately emetogenic therapy (MEC)
Abstract: 11-39-P, Poster Presentation, Friday, June 26, 2015

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients (pts) using anthracycline-cyclophosphamide (AC)-based chemotherapy
Abstract: 11-11-P, Poster Presentation, Friday, June 26, 2015

Pharmacokinetics of rolapitant administered intravenously following single ascending and multiple ascending doses in healthy volunteers
Abstract: 11-20-P, Poster Presentation, Friday, June 26, 2015

Effect of the CYP3A4 inhibitor ketoconazole on the pharmacokinetics of rolapitant, a novel NK-1 receptor antagonist
Abstract: 11-07-P, Poster Presentation, Friday, June 26, 2015

Rolapitant is an investigational product candidate that has not been approved by any regulatory agency.

Advaxis Provides 2015 Half-Year Review and Outlook

On June 25, 2015 Advaxis reported it will hold a business update conference call at 8:30 a.m. ET highlighting year-to-date accomplishments and key near-term goals (Press release, Advaxis, JUN 25, 2015, View Source [SID:1234505803]). The call is intended to provide Advaxis investors and stakeholders with a recap of the Company’s achievements in the first half of 2015 and an overview of milestones anticipated throughout the remainder of the year and into 2016.

A live broadcast of the conference call will be available by direct dial at 1-888-401-4669 in the U.S. or 1-719-325-2458 outside of the U.S.; Conference Passcode 7209396, or by live webcast available online at this URL: View Source

The call will be recorded and available for playback through July 9 by dialing 1-877-870-5176 in the U.S. and 1-858-384-5517 outside of the U.S.; Replay Passcode 7209396. In addition, the webcast will be available for replay at the URL above.

"We are pleased with our accomplishments during the past six months as we continue to strengthen our proprietary immunotherapy platform," said Daniel J. O’Connor, President and CEO of Advaxis. "In addition to the significant progress in R&D, we are financially strong and now have the resources to fully execute on and expand our clinical development programs."

UPCOMING MILESTONES

Advaxis anticipates the following operational milestones throughout the remainder of 2015 and into 2016.

Lm Technology Immunotherapy Clinical Programs:

ADXS-HPV

Commence enrollment in the Phase 3, registration quality trial, AIM2CERV.

Complete enrollment in Stage 2 of the ongoing GOG-0265 Phase 2 trial of ADXS-HPV in persistent or recurrent cervical cancer being conducted by the Gynecologic Oncology Group (GOG), anticipating up to 38 patients enrolled by June 30, 2016 with Final Stage 1 safety and efficacy data to be presented at an upcoming major medical meeting in 2015. Final study data (Stage 1 and 2) to be available in the first half of 2017.

Enroll the first patient this summer in a collaborative Phase 1/2 study of ADXS-HPV in combination with AstraZeneca/MedImmune’s MEDI4736 in cervical cancer and HPV-associated head and neck cancer in second half of 2015 with data available in the first half of 2016.

Complete enrollment in Part A (dose escalation) of our Phase 1 study evaluating higher doses of ADXS-HPV immunotherapy and repeat cycles of treatment with data available from Part A in 2016.

Complete enrollment of the Mount Sinai investigator-sponsored Phase 1/2 study of ADXS-HPV in patients with HPV-associated head and neck cancer. Data to be available in the first half of 2016.

Commence enrollment in a Phase 2 study in patients with HPV-associated metastatic anal cancer by year’s end with data available in the second half of 2016.

Commence enrollment in the second half of 2015 on the Phase 1/2 combination study with Incyte Corporation’s (Incyte) IDO-1 inhibitor.

ADXS-PSA

Complete enrollment in Part A (dose escalation) in the first half of 2016 in the Phase 1/2 study of ADXS-PSA as a monotherapy or in combination with Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab), in metastatic, castration-resistant prostate cancer (mCRPC). Data to be available in second half of 2016.

ADXS-HER2

Enroll the first patient in a Phase 1 first-in-human trial of ADXS-HER2 in metastatic HER2 expressing solid tumors in the second half of 2015 with data to be available in the second half of 2016.
Initiate a clinical study of ADXS-HER2 in pediatric osteosarcoma in partnership with the Children’s Oncology Group (COG) in 2016.
Secure conditional license for ADXS-HER2 (also known as AT-014) for the treatment of canine osteosarcoma from the U.S. Department of Agriculture in 2016.

Business:

Advaxis continues to seek partnerships for its Listeria monocytogenes (Lm) Technology that will enable additional research in combination with other cancer therapies and novel immunotherapies. Advaxis currently retains full commercial rights to its programs.
Advaxis continues to explore options for retaining a Latin American partner for ADXS-HPV to collaborate on co-development and registration in this important region.

FIRST HALF 2015 REVIEW

Since issuing its previous business update in January 2015, Advaxis achieved several regulatory, clinical, business and operational milestones during the first half of 2015.

Lm Technology Immunotherapy Clinical Programs:

ADXS-HPV

GOG’s Phase 2 Study of ADXS-HPV for the Treatment of Persistent or Recurrent Cervical Cancer Achieved Stage 1 Safety and Efficacy Criteria; GOG Began Enrolling Patients in Stage 2 of the Study
On January 28, Advaxis announced that GOG-0265 Phase 2 open-label clinical study of ADXS-HPV in patients with persistent or recurrent cervical cancer with documented disease progression being conducted by the GOG, has completed its first stage and has met the predetermined safety and efficacy criteria required to proceed into the second stage of patient enrollment. The GOG began enrolling patients in Stage 2 of the ongoing Phase 2 trial and expects the study to be fully enrolled by the end of 2015.

Advaxis and GOG to Collaborate on Phase 3 Study of ADXS-HPV in High Risk, Locally Advanced Cervical Cancer; Filed a SPA
On January 7, Advaxis announced a clinical trial collaboration agreement with the GOG for a planned Phase 3 study evaluating the safety and efficacy of ADXS-HPV in high-risk, locally advanced cervical cancer. On June 15, Advaxis announced the submission of a Special Protocol Assessment (SPA) request to the U.S. Food and Drug Administration (FDA) for the Phase 3 study and plans to initiate the study by the end of 2015, depending on the length of the SPA process.

Advaxis Treated First Patient in Phase 1/2 Study of ADXS-HPV for Recurrent Cervical Cancer
On March 19, Advaxis announced that the first patient was dosed in a Phase 1/2 clinical trial evaluating higher doses and repeat cycles of ADXS-HPV in persistent, metastatic or recurrent cervical cancer, based on encouraging survival data seen previously with a lower dose in this patient population.

FDA Cleared IND for Phase 2 Study of ADXS-HPV and Incyte’s epacadostat for HPV-Associated Early Stage Cervical Cancer
On June 1, Advaxis announced the clearance of the Investigational New Drug (IND) application by the FDA to conduct a Phase 2 study of ADXS-HPV alone or in combination with Incyte’s investigational oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, epacadostat, for the treatment of early stage HPV-associated cervical cancer. The trial is expected to begin patient enrollment in the second half of 2015.

Advaxis and RTOG Foundation to Collaborate on a Pivotal Phase 2/3 Study of ADXS-HPV in Anal Cancer
On April 6, Advaxis announced entering into a clinical trial collaboration agreement with the Radiation Therapy Oncology Group (RTOG) Foundation to evaluate the safety and efficacy of ADXS-HPV in a pivotal Phase 2/3 anal cancer trial, which will be run by NRG Oncology.

Preliminary Data from a Phase 1/2 Study of ADXS-HPV in HPV-Associated Anal Cancer Presented at the 2015 IANS Scientific Meeting
On March 16, Advaxis announced that preliminary data from an ongoing Brown University Oncology Research Group investigator-sponsored Phase 1/2 clinical study investigating ADXS-HPV in combination with chemoradiation in HPV-associated locally advanced anal cancer were presented at the International Anal Neoplasia Society (IANS) 2015 Scientific Meeting. Based upon these preliminary data, this study has the potential to transition to a Phase 2/3 registration quality study to be conducted by RTOG.

ADXS-PSA

Advaxis and Merck Initiated Enrollment in the Phase 1/2 Study of ADXS-PSA in Combination with Anti-PD-1 Therapy KEYTRUDA, in Advanced Prostate Cancer
On April 8, Advaxis and Merck announced enrollment has commenced in the Phase 1/2 KEYNOTE-046 clinical trial evaluating ADXS-PSA as a monotherapy and in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in previously treated mCRPC.

ADXS-HER2

FDA Accepted IND for First-in-Human Trial of ADXS-HER2; Advaxis to Initiate Phase 1b Study in Patients with Metastatic HER2 Expressing Solid Tumors
On January 22, Advaxis announced the FDA cleared its IND to conduct a Phase 1b clinical study evaluating the safety and tolerability of ADXS-HER2 as a monotherapy in patients with metastatic HER2 expressing solid tumors. The clinical trial will be the first-in-human study of ADXS-HER2 and is expected to begin patient enrollment in the summer of 2015.

Preliminary Data from Phase 1 Study of ADXS-HER2 in Canine Osteosarcoma Presented at the 2015 AACR (Free AACR Whitepaper) Meeting
On April 20, preliminary data from one clinical and two preclinical studies demonstrating the survival outcomes and anti-tumor effects of Advaxis’s Lm Technology immunotherapies in various settings were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2015. Data from the ongoing Phase 1 clinical study of ADXS-HER2 in combination with palliative radiation suggested that ADXS-HER2 delayed tumor progression and prolonged overall survival in 10 pet dogs with spontaneous osteosarcoma that were not candidates for primary tumor removal (amputation). The commercial rights to the veterinary indications for ADXS-HER2 have been licensed to Aratana Therapeutics.

Business & Operations:

Advaxis Completed Two Successful Rounds of Financing
Advaxis has raised approximately $140 million in fewer than two years and has approximately $100 million in cash on the balance sheet.

Advaxis Completed Leadership Hires In Core Business Functions
Advaxis’s new hires secured leadership positions in manufacturing, regulatory affairs and clinical operations. The industry experience and caliber of these executives highlights that Advaxis has become a company able to attract premier staff from the industry.

Advaxis and Sorrento Formed a Collaboration to Evaluate Combinations of Advaxis’s Lm Technology Product Candidates and Sorrento’s Immunomodulatory Antibodies
Advaxis entered into a non-exclusive research and clinical trial collaboration agreement with Sorrento Therapeutics, Inc. (Sorrento) to evaluate combinations of the company’s immunotherapy candidates, including ADXS-HPV, ADXS-PSA and ADXS-HER2, with Sorrento’s fully human antibodies targeting immune checkpoints, including GITR, OX40, LAG-3 and TIM-3.

Advaxis Formed a Clinical Trial Collaboration With Incyte to Evaluate Investigational Combination of Two Novel Cancer Immunotherapies for Early Stage Cervical Cancer
Advaxis established an agreement with Incyte to investigate the combination of ADXS-HPV together with Incyte’s investigational IDO1 inhibitor, epacadostat. The recently accepted IND for the Phase 2 study evaluating ADXS-HPV as a monotherapy and in combination with epacadostat in patients with early stage HPV-associated cervical cancers is expected to start in the second half of 2015.